Gangliosides are sialylated glycosphingolipids which have been implicated as tumor-associated membrane antigens in tumors of neuroectodermal origin (Hakamori and Kannagi, Int. J. Cancer 71:231-251 (1983)). Examples of such gangliosides are GM3, GD3, GM2 and GD2.
The disialoganglioside antigen GD2 consists of a backbone of oligosaccharides flanked by sialic acid and lipid residues (Cheresh, D. A. 1987, Surv. Synth. Pathol. Res. 4:97). The antigen is highly expressed on tumor cells of neuroectodermal origin including melanoma, neuroblastoma, and small cell carcinoma of the lung (Hakomori, S.-I. and R. Kannagi, 1983, J. Natl. Cancer Inst. 71:231; Cheresh, D. A. et al., 1986, Cancer Res. 46:5112; Mujoo, K. et al., 1987, Cancer Res. 47:1098).
Since GD2 has been shown to be highly expressed on most melanoma cells and its expression in normal cells is mostly restricted to the brain, GD2 is a candidate for vaccine development, especially in combination with other gangliosides (Hamilton et al. Int. J. Cancer 53:566-573 (1993)). The GD2 antigen has also been the target of a number of therapeutic monoclonal antibody trials that have shown some in vivo antitumor effects (Saleh, M. N. et al., 1992, Human Antibodies and Hybridomas 3(1):19; Saleh, M. N. et al., 1992, Cancer Res. 52:4342; Cheung, N.-K. V. et al., 1992, J. Clin. Oncol. 10:671).
Although gangliosides would be useful as vaccines, they are difficult to produce. Furthermore, some gangliosides are only weakly immunogenic. Those that are immunogenic may not be found on all tumor cells. In humans, the GD2 antigen is weakly immunogenic and generally induces T cell-independent humoral immune responses (Tai, T. et al, 1985, Int. J. Cancer 35:607; Portoukalian et al., Int. J. Cancer, 49:893-899 (1991)).
An alternative approach to using the actual ganglioside antigen as a vaccine is to use an anti-idiotypic antibody that mimics the antigen and elicits an immune response. Anti-idiotypic antibodies have been studied as potential vaccines against pathogenic organisms (Kennedy, R. C. et al., 1986, Science 232:220; Reagan, K. J. et al., 1983, J. Virol. 48:660; McNamara, M. K. et al., 1984, Science 226:1325; Sachs, D. L. et al., 1982, J. Exp. Med. 155:1108) and malignant tumors (Chen, Z. J. et al., 1991, J. Immunol. 147(3):1082; Dunn, P. L. et al., 1987, J. Immunol. 60:181-187; Herlyn, D. et al., 1987, Proc. Natl. Acad. Sci. USA 84:8055; Chattopadhyay, P. et al., 1991, Cancer Res. 51:3183). In animal studies, murine anti-idiotypic antibodies have demonstrated antigen-specific responses across species (xenogeneic model) (Chapman, P. B. and A. N. Houghton, 1991, J. Clin. Invest. 88:186) and within the same inbred species (syngeneic model) (Gaulton, G. N. et al., 1986, J. Immunol. 137:2930; Chen, Z. J. et al., 1991, J. Immunol. 147(3):1082; Dunn, P. L. et al., 1987, J. Immunol. 60:181-187; Yamamoto, S. et al., J. Natl. Cancer Inst. 82:1757). The ability of "internal image" anti-idiotypic antibodies to function as immunogens in a syngeneic system implies that the unique CDR epitopes of the anti-idiotypic antibody can be seen as foreign even by animals that otherwise share a very similar antibody repertoire.
The ability of a human anti-idiotypic antibody to elicit both a humoral (B cell) and cellular (cell-mediated) immune response would have significant clinical implications because tumor rejection in vivo is primarily mediated by T lymphocytes (Cerrotini, J. C. and K. T. Brunner, 1974, Adv. Immunol. 18:67; Greenberg, P. D., 1991, In Advances in Immunology, vol. 49, F. J. Dixon, ed. Academic Press, Inc., Orlando, Fla., p. 281). Rarely have anti-idiotypic antibody reagents been shown to possess T cell stimulatory (cell-mediated) activity (Chen, Z. J. et al., 1991, J. Immunol. 147(3):1082). Only one human anti-idiotypic antibody that mimics a tumor associated antigen (TAA) (gp72 colorectal carcinoma antigen) and elicits a T cell response in animals (Austin, E. B. et al., 1989, Immunology 67:525) and humans (allogeneic system) has been reported (Robbins, A. R. et al., 1991, Cancer Res. 51:5425).
Attempts are being made to develop ganglioside anti-idiotypic antibodies. A murine anti-idiotypic antibody that mimics the GD3 antigen has been developed and elicits anti-GD3 antibodies in xenogeneic animals (Chapman, P. B. and A. N. Houghton, 1991, J. Clin. Invest. 88:186). Murine anti-idiotypic antibodies that mimic the melanoma-associated high molecular weight antigen have also been developed and, with the exception of one reagent that induces humoral and cellular immune responses (Chen, Z. J. et al., 1991, J. Immunol. 147(3):1082), all induce B cell immune responses only (Chen, Z. J. et al., 1991, Cancer Res. 51:4790; Chattopadhyay, P. et al., 1991, Cancer Res. 51:6045). Clinical trials using these reagents have yet to conclusively demonstrate anti-tumor immunity. Recently, Yamamoto et al. (Yamamoto, S. et al., J. Natl. Cancer Inst. 82:1757) developed a murine anti-idiotypic antibody that mimics the GM3 antigen.
It is advantageous to provide as many as possible immunogenic anti-idiotypic antibodies that mimic gangliosides and serve as their surrogates in generating an immune response. In addition to other gangliosides being studied as potential anti-idiotypic antibodies, GD2, which is present on a majority of neuroectodermal tumors, is another candidate for an immunogenic anti-idiotypic antibody. An attempt to develop an anti-idiotypic antibody that mimics the GD2 antigen and elicits an anti-GD2 immune response was unsuccessful (Anderson, D. R. and R. E. McCoobery, 1992, J. Immunother. 11:267).
The object of this invention is to provide an "internal image" anti-idiotypic antibody that elicits both humoral and cellular anti-GD2 immune responses in mammals. The immune response should be specifically directed at the unique "internal image" idiotopes present on the anti-idiotypic antibody that mimics the GD2 antigen. Such an anti-idiotypic antibody may be utilized as a vaccine against GD2-expressing tumors.